Angiotensin II is a very potent peptide hormone that causes the muscles surrounding the blood vessels to contract, which thereby significantly narrow the blood vessels. This narrowing increases the pressure within arterial vessels, causing high blood pressure (hypertension). Angiotensin receptor blockers (ARBs) are drugs that block the action of angiotensin II. As a result, arterial vessels dilate and blood pressure is reduced, thereby making it easier for the heart to pump blood. ARBs are therefore used to prevent heart failure as well as hypertension. Drugs in this class include candesartan (Atacand, Astra-Zeneca), eprosartan (Teveten, Solvay & Biovail), irbesartan (Avapro, BMS), losartan (Cozaar, Merck), olmesartan (Benicar, Medoxomil; Sankyo & Forest), telmisartan (Micardis, Boehringer Ingelheim), valsartan (Diovan, Novartis) and pratosartan (Kotobuki). ARBs are used alone or in combination with other classes of antihypertensive agents that include thiazide diuretics, β blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors, both for the treatment of hypertension and congestive heart failure.
Valsartan, a selective ARB, is a well-known antihypertensive agent. Valsartan is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of valsartan is about 25% (10-35%). This relatively low bioavailability of valsartan is primarily due to its poor solubility in the acid milieu of the stomach. Valsartan is an acid, and therefore, has good solubility at pH>5 and low solubility in acidic conditions of the stomach. Valsartan becomes ionized in small intestine and hence cannot get absorbed in ionized form. Valsartan typically gets absorbed rapidly with Tmax in the range of 2-4 hours, however following Cmax the plasma concentration starts reducing reaching to very low level after 10-12 hours.
Pharmaceutically active agents which exhibit low bioavailability unfortunately create a need for frequent dosing of a large amount of pharmaceuticals in order to provide and maintain therapeutic levels. The need for frequent dosing presents patient compliance problems. A need for extended release formulations of valsartan thus arises. Valsartan has low solubility associated with window of absorption, both resulting in poor bioavailability and variability in drug response. Therefore, it becomes important to not only increase the solubility of valsartan but also to take advantage of the window of absorption to increase bioavailability, extend drug release and design true once a day compositions.
Some attempts have been made to provide extended release compositions of valsartan. Design of such extended release formulations of valsartan requires the use of number of different polymers or excipients of varied nature and type. US patent publication 20100233253 discusses a gastro-retentive drug delivery system for delivering valsartan or a pharmaceutically acceptable salt thereof to the stomach, duodenum and upper small intestine of a patient comprising a release portion comprising valsartan and a swellable gastro-retentive portion wherein the swelling of the gastro-retentive portion results in an increase of total volume of the system of less that 50%. PCT Publication WO02009084040A1 discusses a gastro-retentive oral dosage form, comprising an active layer and a gastroretentive layer. The active layer comprises valsartan, solubilizer and at least one release retardant and the gastroretentive layer comprises at least one swelling polymer, at least one swelling enhancer and at least one gas generating agent and optionally an acid source. The gastroretentive dosage form swells in the presence of gastric fluid such that the size of the dosage form is sufficiently increased to provide retention of the dosage form in the upper gastrointestinal tract for a time period of about 30 minutes to about 12 hours. Developing such extended release formulations of the gastroretentive type requiring incorporation of large amounts of swelling type of polymers results in dosage forms that are larger in size than any conventional dosage forms. Such large sized tablets may generally create problems associated with swallowing of the tablets. Coating such tablets to improve swallowability, patient acceptability and compliance therefore becomes imperative. However, coating tablets of extended release type comprising increased amounts of hydrophilic swellable polymers presents numerous challenges.
Various coated solid dosage forms of valsartan have been discussed. US Patent Publication 20130136795 discloses an immediate release solid pharmaceutical composition comprising a core containing valsartan or a pharmaceutically acceptable salt thereof prepared by wet granulation, characterized in that the core has a moisture content of 3% or less and coated with film coating composition which may comprise up to 3% moisture or may be moisture impermeable. US Patent Publication 2011027358 discusses immediate release pharmaceutical tablet composition comprising an effective amount of valsartan prepared by wet granulation, exhibiting satisfactory disintegration properties and coated with one or more non-functional coating layers comprising film forming agents, adhesion promoting agents, coating agents, plasticizers, antitacking agents, coloring agents, opacifiers or mixtures thereof. US Patent Publication 20070166372 discusses a coprecipitate of amorphous valsartan with a pharmaceutically acceptable carrier, wherein the weight ratio of amorphous valsartan to the carrier ranges from 1:0.1 to 0.1:1. The tablet core comprising the coprecipitate is further film coated. The coated solid dosage forms of valsartan discussed are coated primarily with aqueous based film coating compositions, but however do not comprise more than even 10-20% by weight of hydrophilic swelling polymers in the tablet core.
Film coating is generally employed as a method of enhancing the product to positively impact patient preference, differentiating the product's visual appearance, as well as improving the ability to swallow. Aqueous film coating compositions are usually preferred for such coatings. However, depending on the excipients used and type of the dosage form, the aqueous film coating systems have been observed to have detrimental impact on the dosage form, the functions of the excipients used and the final desired performance of the formulation. Particularly, dosage forms of valsartan comprising not less than 25% by weight of core composition of hydrophilic swelling polymers have been observed to be affected by aqueous film coating compositions. The aqueous systems used may affect the properties of the polymers or excipients employed in the dosage forms and thereby such film coated dosage forms may have a rough and uneven surface appearance, reducing patient acceptability. The extended release formulations of valsartan of the gastroretentive type may also incorporate an effervescent couple comprising a gas generating agent and an acid source. Aqueous based film coating tends to impact the performance of such an effervescent couple as well. The impact of aqueous film coatings on the coated valsartan tablets discussed above may not be evident considering the type of those formulations and the type of excipients and amounts thereof they use. However, for systems of valsartan of the extended release type comprising high amounts of swelling polymers, aqueous based film coating systems can have detrimental impact on the desired function, appearance as well as release and gastroretentive profile of the dosage forms.
A need thus exists for development of coated extended release dosage forms of valsartan that have excellent physical appearance, increased patient acceptability and desired release and gastroretentive performance. The present inventors after in-depth research developed extended release coated formulations of valsartan comprising a core of valsartan and at least one swelling hydrophilic polymer and at least one coating layer over the core wherein the coating layer in contact with the core is applied using at least one organic solvent based coating composition.
The present inventors further also developed extended release coated formulations comprising a core of valsartan and a dual layer film coating system, that overcomes the problems associated with application of direct aqueous coating systems on extended release core tablets of valsartan, particularly core tablets comprising high amounts of swelling polymers. The present inventors have developed coated extended release formulations of valsartan comprising an extended release valsartan core and dual layer coating system comprising an inner organic seal coat layer in contact with the core and an outer aqueous film coating layer. Such dual coated extended release dosage forms of valsartan are aesthetic in appearance and have desired release and/or gastroretentive properties and excellent smooth surface, thereby enhancing patient acceptability and swallowability.